Genetic counseling: Alpha 1 Antitrypsin Deficiency
Alpha 1 Antitrypsin Deficiency Introduction *Acknowledge any prior contact *Assess concerns and questions they have *Explain that their concerns will be addressed Elicit Family History and Pedigree Elicit Medical History *Include information about environmental/occupational hazards and smoking What is Alpha 1 Antitrypsin Deficiency (ATT deficiency)? *Alpha-1 antitrypsin deficiency is an inherited disorder that causes low levels of, or no alpha-1 antitrypsin in the blood. *Alpha-1 antitrypsin is a protein that is made in the liver. The liver releases this protein into the bloodstream. *The deficiency of this protein may predispose an individual to several illnesses **The most common illness in adults with alpha 1 antitrypsin deficiency is lung disease during the third and fourth decades of life. This is earlier than in those without the deficiency ***Most commonly it is associated with chronic obstructive pulmonary disease (COPD). ***COPD is characterized by coughing, shortness of breath, sputum production, rapid breathing, wheezing, and weight loss due to the energy required for labored breathing. ***COPD includes chronic bronchitis and emphysema ****chronic bronchitis - inflammation of the lining of the bronchial tubes ****emphysema - permanent destruction of the alveoli ***AAT Deficiency is the most common genetic cause of emphysema. It is also the most frequent cause of disability and early death among affected people. ***Less commonly AAT deficiency may cause progressive liver damage (cirrhosis) or liver cancer. ***15-25% of affected patients develop cirrhosis and its complications, but 75% of individuals will not have any significant liver disease after the newborn period ***Some patients with cirrhosis lead relatively normal lives for relatively long periods of time ***Some patients have serious liver damage that requires a liver transplant. ***Less than 3% may develop cancer of the liver. *Alpha-1 antitrypsin deficiency is the most common genetic cause of liver disease in children and is the most common genetic disease for which liver transplantation is undertaken in children. **Some children show signs of liver failure at birth including jaundice, swelling of the abdomen, and poor feeding **In some children, the signs of alpha-1 antitrypsin deficiency do not become apparent until early childhood or adolescence when they may develop hepatitis, enlarged spleen, ascites, pruritus and other signs of liver injury. **Only 10-15% of children with alpha-1 antitrypsin deficiency develop liver disease. In some families one child may not show any signs of liver disease whereas a brother or sister may be seriously affected. *It is possible to have AAT deficiency without having developed symptoms yet or that has been misdiagnosed. *The reasons for the wide variability, from normal life span and normal activity through life, to severe liver or lung disease are largely unknown. Who is at risk? *An estimated 1 in 1500 to 1 in 7000 people has alpha 1 antitrypsin deficiency world wide and it is found in nearly all populations. *It is very rare among people of Asian and African descent. *It is most prevalent among people of Northern European (Scandinavian and British) and Iberian (Spanish and Portugese) descent. *100,000 people are estimated to be affected in the U.S., and a similar number in Europe are thought to be affected *Of the estimated 100,000 in the U.S. only 10% have been diagnosed *Some researchers believe that it is more common than Cystic Fibrosis *It is thought that AAT deficiency is widely underdiagnosed or misdiagnosed as asthma or cigarette smoking induced COPD. *Estimated carrier frequencies in the above mentioned at risk populations have been quoted as high as 1:25 *Research suggests that some carriers may be at increased risk for lung disease at a later age of onset. *Other more current research suggests that being a carrier is not a very important determining factor compared to other risks such as smoking. How does a deficiency lead to lung disease? *Alpha-1 antitrypsin protects the lungs against another protein that can harm lung tissue. (It is called neutrophil elastase-- an enzyme released by white blood cells to help fight infections) *When the lungs do not have enough alpha-1 antitrypsin, these proteins are free to destroy lung tissue. *As a result, the lungs lose some of their ability to expand and contract (elasticity) *This leads to difficulty breathing. *Destruction of the alveoli can also occur and lead to emphysema *The speed at which lung tissue is destroyed varies with each person. *It is known that tobacco smoking worsens the lung damage. How does a deficiency lead to liver disease? *Individuals with AAT deficiency often do not secrete AAT after it is made by the liver. *Some of the AAT is broken down but the portion that is not accumulates in the liver cells. *This accumulation can damage the liver and lead to cirrhosis. How is it inherited? *Alpha 1 antitrypsin deficiency is an autosomal recessive genetic condition *Explain genes and chromosomes *Alpha 1 antitrypsin is encoded by a gene (PI) located on the distal long arm of chromosome 14. *There are at least 75 different variations, or alleles, of the gene that make alpha 1 antitrypsin. *We get one copy of this gene from each of our parents *The M allele is the most common form (actually there are a group of M alleles along with other very rare normal variants) *If a person inherits an M gene from both their parents they will have normal levels of alpha 1 antitrypsin (MM genotype) *The Z gene is altered. As a result there is not as much alpha 1 antitrypsin into the blood. *The protein formed from the Z allele has a glu changed to a lys *This causes misfolding of the polypeptide *Decreased ability for normal protein folding leads to accumulation of abnormal protein in hepatocytes some of which is subsequently degraded *When a person inherits the Z gene from both parents they will have very low alpha-1 antitrypsin levels that can lead to tissue damage of the lungs and/or liver disease (ZZ genotype) *If a person inherits one M gene and one Z gene they are called a carrier. Although they usually have less alpha 1 antitrypsin in their blood then those with two M genes, they do not usually develop any symptoms because they still have sufficient amounts to protect their lungs. *MZ phenotype was associated with an increased prevalence of byssinosis compared with the MM phenotype: 3/8 (38%) and 25/187 (13%). An association between the MZ phenotype and familial allergy was also found, although the association was somewhat weaker. *5% of Scandinavians, 4% of Britains, 1 to 2% of southern Europeans, and 2-3% of the heterogeneous white population in the United States are MZ (carriers) heterozygotes. *If both parents are carriers for the Z allele than their children each have a 25% chance of having a child at risk for lung and liver disease *The S variant of this gene makes functional alpha 1 antitrypsin, but it is broken down and made nonfunctional more easily before it is secreted. *If a person inherits two copies of the S variant than their alpha 1 antitrypsin levels are reduced but they don't show any symptoms *If a person inherits one S and one Z variant they have a mildly increased risk for lung disease. *There is a relatively high frequency of the S allele (0.04-0.08 in U.S. Caucasians). Therefore MS heterozygotes are relatively frequent. *1 in 10 persons of European origin will be heterozygous for either the S or Z variant (MZ or MS genotype) *About 5 % of people with alpha 1 antitrypsin deficiency will have other rare allele variants. *In some rare cases, a person's body may not produce any alpha-1 antitrypsin. This condition results from inheriting two genes that don't allow any functioning protein to be made. It is called "null-null type." *The null-null phenotype is accompanied by emphysema as are the ZZ and SZ phenotypes but an important difference is that cirrhosis and liver cancer do not occur with the null-null phenotype because there is no abnormal antitrypsin product accumulation Who should be tested? *The World Health Organization (WHO) recommends that all individuals with COPD as well as adults and adolescents with asthma be tested. *Clinical features that suggest the possibility of AAT deficiency and the need for serum testing include emphysema at an early age, emphysema in a nonsmoker (or light smoker), a family history of emphysema, emphysema of the lower lungs (as determined by chest radiograph), adult-onset asthma, and recurrent bronchitis. *It is also suggested that testing be done on most patients with chronic or recurrent respiratory symptoms (dyspnea, cough, wheezing) at least once. *It has been suggested that carrier screening should be performed on people in high- risk populations. What is the test? *It is a simple blood test that can be done on a finger stick or venous blood sample *It will determine the amount of AAT in your blood (blood enzyme levels) **Serum testing is a screening procedure. Most hospital laboratories report serum AAT levels in mg/mL, with a normal range from approximately 100-300 mg/mL. Levels less than 80 mg/mL suggest a significant risk for lung disease. **Reference laboratories usually report the serum levels in micromolar concentration, with a normal range of 20-60 micromol/L and a threshold level for emphysema at 11 micromol/L. *The same blood sample can also be used to determine which type of protein (the phenotype) you have **Therefore the phenotype test can tell you if you are a carrier for one of the genes that causes alpha 1 deficiency **The phenotype is usually determined if alpha 1 antitrypsin levels are below 30 micromoles/ liter or if there is a known family history **Therefore, to detect all heterozygous carriers it is important to make sure the lab performs phenotype testing. **Phenotyping is required to confirm the presence of AAT deficiency. Do not initiate AAT replacement therapy without testing. **The phenotype, PiZZ, is responsible for nearly all cases of AAT emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 micromol/L, about 10-20% of the normal levels. Where is testing available? *Free test kits are available through the Alpha-1 Foundation and they take 2-4 weeks for the order to be processed. They test for both levels of protein and phenotype so carrier status can be determined *Information and an order form is attached *It will take about two weeks to get the results back *Free genetic screening kits are also available through Bayer Laboratories at 800-288-8371, and samples can be processed for free at the AAT Deficiency Detection Center, University of Utah, 801-328-4662 *Confidential testing is also available *Information about this is also attached *I attempted to contact the Cleveland Clinic foundation for information on testing, but they didn't return my call. Their number is 1-800-223-2273, ext. 43702 *Other labs which perform testing are also included, but I didn't contact them Reasons for being tested *There are ways to help prevent tissue damage in the lung such as: **receive immunizations for flu and pneumonia **receive early treatment for lung infections by seeing your doctor at the first sign of a cold or other lung problem **avoid tobacco smoke, noxious fumes, dust, and pollution **stay fit by doing regular exercise **increase your alpha-1 antitrypsin by enzyme replacement therapy (intravenous infusion of the purified human enzyme (Prolastin) used to treat patients with the PiZZ, Piz(null), or Pi(null)(null) phenotypes.) *Information about this is attached. *You can also reduce symptoms of shortness of breath by doing the following: **using medications (for example, bronchodilators, or inhaled steroids) prescribed by your doctor to help open your airways **using oxygen if your doctor prescribes it **doing pulmonary rehabilitation (including breathing techniques) Family planning (knowing risks to future children) *As of 1987 prenatal testing is available for fetuses known to be at risk *Gene therapy in the future? Research has been done in mice using gene therapy for AAT deficiency Possible reasons for not being tested *There is a reported case where a person lost their job after receiving a bill for treatment procedures in a woman with a positive test for alpha 1 antitrypsin deficiency *She was supported by the AlphaNet, the Alpha 1 Association, the Genetic Alliance, the National Partnership for Women and Families and the Coalition for Genetic Fairness *She won the right in Nov 2000 to pursue a wrongful discharge law suit. *Concerns about this may be avoided by confidential testing Other psychosocial issues to consider *Anxiety associated with waiting for test results *Anxiety and difficult decisions associated with knowing you and your partner are carriers and may pass alpha 1 antitrypsin deficiency on to offspring *Anxiety that may come if testing positive for AAT deficiency in the absence of present symptoms due to the uncertainty about how severely one will be affected. References *Fleming et al. (2001). Pilot Deficiency Study of Alpha 1 Antitrypsin Deficiency in Targeted Population. American Journal of Medical Genetics. 103:69-74 *Alpha one foundation website(testing information and patient resource) *patient resources (information and support group it is in Spanish also) *website (contains great patient information that is easy to understand on signs and symptoms of the disorder as well as risk factors and treatment) *child liver disease(good patient resource about liver disease in children) *website (all of the in depth scientific information about the various types of alleles and review of research done) *website *website(genetic discrimination case relating to alpha 1 antitrypsin deficiency) *website *website (information about lung disease and testing) *website (AlphaNet is a not-for-profit health management company founded by Alphas to provide comprehensive services for alphas.) *website *website Tables Notes The information in this outline was last updated in 2001. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling